This is a multi-institutional program grant that develops a CLL Research Consortium (CRC) that will research the biologic basis of CLL and investigate novel biologic and pharmacologic treatments for this disease. The CRC will establish a muti-institutional CLL Clinical Consortium to enable uniform, high-volume sample accrual and inter-institutional phase I/II clinical studies. This will allow the CRC to research novel treatments for CLL, and to examine for clinical<->laboratory relationships that ultimately may permit improved clinical staging and/or assist in the evaluation of the response to novel therapies. Furthermore, the CRC will develop and maintain an interactive Website for CRC investigators (see: http://orpheus.ucsd.edu/hemonc/cllcghome.htm), a sophisticated national tissue bank, and a secured on-line relational database that will allow for basic and clinical research studies on disease heterogeneity among patients with CLL, or in any one CLL patient over time. Finally, the CRC will develop a Clinical Advisory Committee that can advise established cooperative groups on the relative merits of novel treatment strategies being considered for phase III testing. The grant has six major projects. Project 1 (Croce PI) investigates the genetic basis for CLL. Project 2 (Reed PI) investigates the leukemia-cell expression of genes and proteins important in the regulation of apoptosis and in defining the leukemia cells' resistance to pharmacologic or biologic therapy. Project 3 (Kipps PI) examines novel techniques for active immunotherapy of this disease, including those involving gene transfer and/or leukemia-purged autologous stem cell transplantation. Project 4 (Gribben PI) examines the potential for autologous or allogeneic adoptive immunotherapy of CLL. Project 5 (Plunkett PI) examines some of the most promising lead compounds for phase I/II testing CLL and examines the mechanisms of action of these agents acting alone or in mechanism-based combinations, Project 6 (Keating PI) examines for treatment strategies that can achieve remission and assesses the value of parameters that may serve as prognostic indicators in CLL. In addition, this project establishes the CLL Clinical Consortium (CCC). The CRC has 3 cores: Core A (Kipps PI) is the administrative core that will coordinate research investigations, oversee the generation and maintenance of the clinical and laboratory databases, maintain the CRC Website and listserver, and organize meetings and teleconferences between members of the project and outside reviewers. Core B is the Biostatistics Core (Neuberg PI) that will assist investigators in the biostatistical design and implementation of basic and clinical research projects. Core C (Rassenti PI) is the Tissue Core. This core is responsible for tissue banking, sample trafficking, and leukemia sample laboratory testing and sample-validation. Through this CRC we will expedite research aimed at achieving a better understanding of the biologic basis of this disease and its eventual cure.